Breastcanceris among the most commonformsof cancerwithover 180,000 newcases diagnosed inthe USA each year. Approximatelyhalf of all breastcancerpatientsdie from the diseasebecause metastaticbreastcancer remainsa generallyincurableandfatal disease.Cytotoxicdrugtreatment is an importantweapon againstcancer.However, cancerouscellsfrequentlydevelopdrug resistanceto these agents.We have determinedthat activationof the Ras/Raf/MEWERK signal transductioncascadewill lead to an increasedabilityof MCF-7 breastcancercellsto proliferatein the presenceof the chemotherapeuticdrugsdoxorubicinand paclitaxel.Consequencesof Raf activationmay includeincreasedexpressionof the drugtransportermdr-1, the anti-apoptoticbcl-2 gene, and autocrinegrowthfactorssuchas suchas amphiregulinwhichbindthe HER2 growth factor receptorimplicatedin the etiologyof breastcancer.In the proposedstudies,we will determinewhether inductionof mdr-1, bcl-2and autocrinegrowthfactor expressionbythe Ras/Raf/MEWERK signaltransductionpathwayis essentialfor inductionof breastcancerdrug resistanceandthe mechanismsby whichthisoccurs.To achievetheseobjectives,threespecific aims have been proposed:Aim 1. To determinemechanismsby whichthe Ras/Raf/MEWERK pathwayregulatesmdr-1, bcl-2, and autocrinegrowthfactors andwhethertheirinducedexpression is requiredfor breastcancerdrugresistance,Aim 2. To determinemechanismsby whichthe Ras/Raf/MEWERK and Ras/PI3K/PTEN/PDK/Akt pathwaysinteractand regulatemdr-1, bcl-2and breastcancerdrugresistance.Aim 3. To determinemechanismsbywhich Ras/Raf/MEWERK pathwayinfluencesthe redoxstatusof breastcancercellsto modulatetheirsensitivityto chemotherapeuticdrugs.Throughthese studies,moreinformationwillbe availableto treatbreast andothercancerpatientswithcombinationsof drugs,whichinhibitsignaltransductionand anti-apoptoticpathwaysleadingtodrug resistance.